The present invention generally relates to automated systems and methods for processing chemicals dissolved in solvents and for rapidly identifying chemicals with biological or toxic activity in liquid samples, particularly automated methods of reformating samples and the aspiration and dispensation of potential new medicines, agrochemicals, and cosmetics.
Systems and methods for rapidly identifying chemicals with biological or toxic activity in samples, especially small liquid samples, can benefit a number of different fields. For instance, the agrochemical, pharmaceutical, and medical diagnostics fields all have applications where large numbers of liquid samples containing chemicals are processed. Currently, many such fields use various strategies to reduce processing times, such as simplified chemistry, semi-automation and robotics. While such strategies may improve the processing time for a particular single type of liquid sample, process step or chemical reaction, such methods or apparatuses can seldom efficiently process many thousands of dissimilar samples, for example as found in a chemical library, or in a nucleic acid array. As the size of chemical libraries and nucleic acid arrays has grown, the rate at which complex libraries can be accurately distributed for testing or analysis has become rate-limiting. In particular, there is a need to develop methods and devices that can rapidly process many thousands of different samples and accurately and reproducibly distribute or redistribute known amounts of those samples for further analysis. Central to this need is a requirement to efficiently handle a multitude of different liquid samples, such as chemical or nucleic acid libraries present in chemical or sample multiwell plates of varying densities and formats.
Multiwell plates may be orientated and configured in a variety of designs and formats and be present either with, or without, lids. For example, multiwell plates, commonly known as xe2x80x9cmicroplatesxe2x80x9d, have been in common use for decades with a predominant format being a molded plastic multiwell plate having 96 sample wells in an 8xc3x9712 rectangular array. Typical well volumes are 200 or 300 microliters, depending upon the manufacturer and model of multiwell plate, although other volumes may be provided for specific uses, for example see Whatman/Polyfiltronics 1998 Microplate Product Guide. Polyfiltronics Inc., 136 Weymouth Street, Rockland, Mass. 02370 USA. A proposed standard, designated xe2x80x9cMicroplate 96-Well Standardxe2x80x9d (MP96) has been promulgated by The Society for Biomolecular Screening, as published in Journal of Biomolecular Screening, Volume 1, Number 4, 1996, the disclosure of which is incorporated herein by reference. A multiwell plate which meets the general dimensional requirements of the standard is designated MP96-3. Typically, each multiwell plate manufacturer will also provide a compatible lid. A typical lid comprises a generally rectangular flat planar top surrounded by a flange depending from the top along its sides and edges.
Multiwell plates are used for many different types of applications, including chemical library generation and storage, additionally multiwell plates may also be used to hold arrays of polynucleotides for use in expression analysis, or genomic analysis, as described in for example, Schena (1996) Genome analysis with gene expression microarrays BioEssays 18 no 5 427-431; Johnson (1998), Gene chips: Array of hope for understanding gene regulation Current Biology 8 R171-R174; Scholler et al. (1998) Optimization and automation of fluorescence-based DNA hybridization for high-throughput clone mapping Electrophoresis 19 504-508. Multiwell plates may also be used for gene amplification using the polymerase chain reaction as described in U.S. Pat. No. 5,545,528 entitled Rapid Screening Method of Gene Amplification Products in Polypropylene Plates.
The advent of high throughput analysis and increasing use of miniaturized formats has also lead to the development of higher format multiwell plates for example, 384, 864 and 3456 wells as described in PCT patent application identified by serial number PCT/US98/11061 entitled Low Background Multi-Well Plates With Greater Than 864 Wells for Fluorescence Measurements of Biological and Biochemical Samples, published Dec. 2, 1998. Even higher density sample processing systems, for example using chips that contain miniaturized microfluidic devices are being developed (see for example, Marshall (1998) Lab-on-a Chip: Biotech""s Next California Gold Rush R and D Magazine, November 1998, pages 38 to 43).
Higher density multiwell plates enable faster analysis and handling of large sample or chemical libraries, such as in automated screening systems. However, irrespective of the final plate density, the inventors have often recognized that the overall throughput of the system is limited by the requirement to distribute chemical solutions from multiwell plates with a first well density to a second well density, particularly when the second well density is greater than 96 wells per plate. The need thus exists for a chemical solution distribution system that can rapidly and accurately process liquid samples on multiwell plates of different densities, particularly those with densities of greater than 96 wells per plate.